Regulation of beta-cell homeostasis by DNA methylation and hydroxymethylation.

通过 DNA 甲基化和羟甲基化调节 β 细胞稳态。

基本信息

批准号：
10557897
负责人：
Sangeeta Dhawan
金额：
$ 43.25万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557897
关键词：
Address Affect Age Animals Antioxidants Ascorbic Acid Beta Cell Cell Cycle Cell Differentiation process Cell physiology Cells Citric Acid Cycle Complex DNA DNA Methylation DNA Modification Methylases DNMT3a Data Defect Development Diabetes Mellitus Diabetic mouse Disease Disease Progression Disease model Embryo Endocrine Environment Environmental Risk Factor Enzymes Epigenetic Process Equilibrium Exposure to Failure Functional disorder Glucose Goals Growth and Development function Health Homeostasis Human Hydroxylation Impairment Insulin Insulin-Dependent Diabetes Mellitus Link Maps Mediating Metabolic Metabolism Methods Mus Nature Neonatal Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pancreas Pattern Persons Phenotype Polycomb Predisposition Public Health Publishing Regulation Regulatory Pathway Rejuvenation Research Role Shapes Stimulus Testing Tissues United States Variant Work age related alpha ketoglutarate antagonist beta cell replacement betacell therapy cofactor defined contribution demethylation diabetes mellitus therapy diabetes pathogenesis diabetes risk diabetic endocrine pancreas development epigenetic profiling epigenome functional loss genome-wide improved insulin secretion interest islet methylation pattern mouse genetics mouse model novel preservation progenitor response self-renewal stem cells therapeutically effective type I and type II diabetes

项目摘要

PROJECT SUMMARY/ABSTRACT Diabetes has become a major public health crisis, afflicting nearly 30 million people in the United States, and these numbers continue to rise at an alarming rate. Both type 1 and type 2 diabetes result from insulin insufficiency, in large part due to loss of functional beta-cells. Significant research efforts are currently focused on understanding beta-cell failure in diabetes, and developing effective therapeutic approaches to replenishing the beta-cell deficit in diabetes. Despite significant advances in these aspects, challenges remain in development of effective beta-cell therapies, primarily due to gaps in our current understanding of mechanisms that regulate normal beta-cell development, function, and growth. Our recent work has identified DNA methylation as a pivotal epigenetic mechanism that regulates beta-cell identity and function. Moreover, we found that DNA methylation patterns defining functional beta-cell phenotype are disrupted in the diabetic beta-cells, suggesting dynamic nature of DNA methylation. Our preliminary studies indicate that dynamic remodeling of DNA methylation (5- methylcytosine; 5mC) via its conversion to a hydroxylated form (5-hydroxymethylcytosine; 5hmC) is essential for beta-cell differentiation, function, and adaptive response. We hypothesize that stage-specific, appropriate patterning of 5mC and 5hmC is critical for beta-cell homeostasis, and is disrupted in diabetes leading to beta- cell failure. Thus, we seek to determine how enzymatic regulation of the balance between 5mC and 5hmC governs functional beta-cell mass and affects diabetes susceptibility. We will employ mouse genetics, disease models, human islet studies, and state-of-the-art genome wide epigenetic profiling methods to address the following aims: In Specific Aim 1, we aim to establish the requirement of 5mC and 5hmC patterning in differentiation of beta-cells from progenitors. Specific Aim 2 seeks to define the contribution of dynamic remodeling of 5mC and 5hmC patterns in beta-cell replication and adaptive capacity. In Specific Aim 3, we address if and how environmental factors like oxidative stress and metabolite variation can disrupt the beta-cell 5mC 5hmC landscape to drive beta-cell failure, and diabetes. The proposed studies will delineate a novel regulatory module that governs beta-cell development and growth, and establish a fundamental regulatory paradigm that link beta-cell environment, metabolism and epigenome. Our work is likely to have a broad and significant impact by providing novel clues to promote beta- cell differentiation, function, and expansion towards strategies aimed at beta-cell rejuvenation and replacement for diabetes therapy.

项目摘要/摘要糖尿病已成为主要的公共卫生危机，在美国遭受了近3000万人的困扰，并这些数字继续以惊人的速度上升。 1型和2型糖尿病是由胰岛素引起的不足，在很大程度上是由于功能β细胞的损失。目前重点的重大研究工作了解糖尿病中的β细胞衰竭，并开发有效的治疗方法来补充糖尿病中的β细胞赤字。尽管这些方面取得了重大进展，但挑战仍在发展中有效的β细胞疗法，主要是由于我们当前对调节机制的理解的差距正常的β细胞发育，功能和增长。我们最近的工作已将DNA甲基化确定为关键调节β细胞身份和功能的表观遗传机制。此外，我们发现DNA甲基化定义功能性β细胞表型的模式在糖尿病β细胞中被破坏，表明动态 DNA甲基化的性质。我们的初步研究表明，DNA甲基化的动态重塑（5- 甲基胞嘧啶; 5MC）通过其转化为羟基化形式（5-羟基甲基胞嘧啶; 5HMC）对于对 β细胞分化，功能和自适应响应。我们假设那个阶段特定的，适当的 5MC和5HMC的构图对于β细胞稳态至关重要，并且在糖尿病中破坏了β- 细胞衰竭。因此，我们试图确定如何对5MC和5HMC之间平衡的酶促调节控制功能性β细胞质量并影响糖尿病的敏感性。我们将采用小鼠遗传学，疾病模型，人类胰岛研究和最先进的基因组广泛的表观遗传分析方法来解决以下目的：在特定目标1中，我们旨在确定5MC和5HMC图案的要求 β细胞与祖细胞的分化。特定目标2试图定义动态的贡献在Beta细胞复制和适应能力中重塑5MC和5HMC模式。在特定的目标3中，我们解决氧化应激和代谢物变化等环境因素是否以及如何破坏β细胞 5MC 5HMC景观以驱动β细胞衰竭和糖尿病。拟议的研究将描述一个新型的监管模块，该模块控制β细胞的发展和增长并建立一个基本的监管范式，将β细胞环境，代谢和表观基因组。我们的工作可能通过提供新的线索来促进β- 细胞分化，功能和扩展针对旨在Beta细胞恢复和替换的策略用于糖尿病治疗。